Approximately 25% of patients responding to treatment for initial cases of Clostridium difficile infection (CDI) develop a recurrence of the infection, and many develop multiple recurrences. Unfortunately, the optimal medical management of recurrent CDI is unclear. In particular, vancomycin taper and pulse regimens are commonly used, but have not been compared to other medical treatments in randomized trials. To address this deficiency, the VA Cooperative Studies Program (CSP) is conducting a randomized trial, CSP596, to compare a standard 10-day course of vancomycin versus 10 days of fidaxomicin versus 10 days of vancomycin followed by a vancomycin taper and pulse regimen for first or second recurrences of CDI. We propose to conduct a sub-study of the CSP trial to develop a better understanding of the microbiologic impact of the treatment regimens. The central hypothesis of the proposal is that taper and pulse treatment regimens facilitate clearance of spores from the colon while allowing recovery of intestinal microbiota that provide colonization resistance to C. difficile. Our first specific aim is to compare the composition of the indigenous intestinal microbiota and clearance of C. difficile in patients receiving treatment with vancomycin taper and pulse regimens versus standard vancomycin or fidaxomicin regimens for recurrent CDI. To accomplish this aim, we will collect stool specimens before, during, and after treatment for a subset of 120 participants in the VA CSP trial (~40 per treatment group). We will compare the composition of the microbiota and the presence and concentration of C. difficile in stool of patients in each treatment group. Our second specific aim is to determine if pulse dosing of vancomycin and fidaxomicin enhances clearance of C. difficile spores. To accomplish this aim, we will use a mouse model of C. difficile colonization to compare clearance of C. difficile spores and recovery of the microbiota with every 2 or 3-day pulse dosing of vancomycin or fidaxomicin in comparison to daily dosing for the same treatment duration and to the standard 10-day treatment regimens used in the CSP# 596 trial. The results will be significant because recurrent CDI is an important clinical challenge and there is an urgent need for effective management approaches.